Innovative Way to Combat Fungal Infections Discovered

Tuesday - August 8 2023, 01:42 UTC - 1 year ago

Researchers from the RIKEN Center for Sustainable Research Science (CSRS) and the University of Toronto have discovered an innovative way to combat fungal infections. They identified a natural product, NPD6433, from the RIKEN natural product depository that works by inhibiting fatty acid synthase, preventing the synthesis of fatty acids within fungal cells. Experiments have found it effective against a wide range of fungi, including Candida, Cryptococcus, and Aspergillus species, as well as the model organism Caenorhabditis elegans. The team recommends their discovery as part of an arsenal for anti-fungal drugs.

Researchers at the RIKEN Center for Sustainable Research Science (CSRS) and the University of Toronto have discovered an innovative way to combat fungal infections. This method revolves around obstructing the fungi’s ability to produce fatty acids, a primary component of fats. With resistance to anti-fungal drugs increasing, this new tactic, which works differently and is effective against a wide range of fungal species, could prove particularly beneficial. The study was published in the scientific journal Cell Chemical Biology.

Most people are familiar with athlete’s foot, a relatively benign health issue easily resolved with a trip to the drugstore. However, other fungal infections, caused by Candida, Cryptococcus, and Aspergillus types of fungi, are far more serious. In fact, these fungi are responsible for millions of deaths every year. Like bacteria’s growing resistance to antibiotics, resistance to anti-fungal medications is also on the rise globally. Consequently, the death toll is likely to increase in the foreseeable future without immediate intervention.

Presently, only three primary classes of anti-fungal medications exist. All of them function by breaking down the barrier surrounding fungal cells. Interestingly, even though all current treatments target the cell barrier, they are surprisingly species-specific. This specificity implies that a drug effective against one species of fungus might not work on another.

The team of researchers sought an alternative strategy to combat harmful fungi, one that could target multiple species. Their approach was to first screen the structurally-diverse RIKEN natural product depository (NPDepo) against four pathogenic yeasts. These include three Candida and one Cryptococcus species, identified by the World Health Organization as critical human pathogens. They aimed to find an agent that would affect all four species, suggesting it could be effective against a broad spectrum of fungi.

The screening identified several compounds that decreased fungal growth by at least 50% in each of the four species. After eliminating known substances, three new possibilities remained. Among these, the one that was least toxic to human cells also inhibited the growth of Aspergillus fumigatus, a prevalent and deadly fungal mold for immuno-compromised individuals. This compound, named NPD6433 in the RIKEN NPDepo, then underwent further analysis to determine its mechanism of action.

For almost 1000 different genes, the scientists assessed how much NPD6433 suppressed growth in yeast when the yeast was missing one copy of the gene. They discovered that the reduction in only one gene, fatty acid synthase, heightened the yeast’s susceptibility to NPD6433. This indicated that NPD6433 likely functions by inhibiting fatty acid synthase, preventing the synthesis of fatty acids within fungal cells. Subsequent experiments demonstrated that NPD6433 and cerulenin, another fatty acid synthase inhibitor, were capable of exterminating numerous yeast species in culture.

In the final experiment, the researchers tested NPD6433’s efficacy in a live laboratory model organism—the worm Caenorhabditis elegans. With the emergence of drug-resistant fungi, NPD6433 represents a promising tool for fungal control. It’s capable of killing a wide range of fungi, while cerulenin shows promise against Aspergillus. The team recommends their discovery as part of an arsenal for anti-fungal drugs.